[NO3], a green and base-free medium for one-pot synthesis of benzothiazinones at room temperature

Article abstract of DOI:10.1080/00397911.2012.687422

A general and efficient room-temperature procedure is developed for high-yield synthesis of 2H-benzo[b][1,4]thiazin-3(4H)-one derivatives in one pot from the reaction of 2-aminothiophenols with 2-bromoalkanoates in ionic liquid [bmim]NO₃ without the use of any catalyst, base, or additive. Products were obtained in good yields by simple extraction with Et₂O followed by evaporation of the volatile contents and recrystallization from Et₂O. The ionic liquid was recycled and reused in the next reaction without the loss of its activity.

Full text of DOI:10.1080/00397911.2012.687422

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[Omim][NO3], a Green and Base-
Free Medium for One-Pot Synthesis of
Benzothiazinones at Room Temperature
Ali Sharifi a , M. Saeed Abaee a , Mahdiyeh Rouzgard a & Mojtaba
Mirzaei a
a Chemistry and Chemical Engineering Research Center of Iran,
Tehran, Iran
Accepted author version posted online: 22 Jan 2013.Published
online: 28 Apr 2013.
To cite this article: Ali Sharifi , M. Saeed Abaee , Mahdiyeh Rouzgard & Mojtaba Mirzaei (2013):
[Omim][NO3], a Green and Base-Free Medium for One-Pot Synthesis of Benzothiazinones at Room
Temperature, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:15, 2079-2089
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Synthetic Communications1, 43: 2079–2089, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.687422
[Omim][NO3], A GREEN AND BASE-FREE MEDIUM
FOR ONE-POT SYNTHESIS OF BENZOTHIAZINONES
AT ROOM TEMPERATURE
Ali Sharifi, M. Saeed Abaee, Mahdiyeh Rouzgard, and
Mojtaba Mirzaei
Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract A general and efficient room-temperature procedure is developed for high-yield
synthesis of 2H-benzo[b][1,4]thiazin-3(4H)-one derivatives in one pot from the reaction
of 2-aminothiophenols with 2-bromoalkanoates in ionic liquid [bmim]NO3 without the use
of any catalyst, base, or additive. Products were obtained in good yields by simple extraction
with Et2O followed by evaporation of the volatile contents and recrystallization from Et2O.
The ionic liquid was recycled and reused in the next reaction without the loss of its activity.
Keywords 1,4-Benzothiazin-3-ones; green chemistry; heterocyclization; ionic liquids
INTRODUCTION
Along with the worldwide increase in environmental safety enforcement,
ionic liquids (ILs) have been recognized as useful green media in various fields of
chemistry.[1] In particular, chemists can tailor ILs with desired physical and chemical
properties to boost the selectivity and reactivity of various synthetic transforma-
tions.[2] Consequently, ILs are known nowadays as environmentally benign surro-
gates for conventional organic solvents because they are easily recoverable, have
very low vapor pressure, exhibit increased thermal stability, are able to dissolve a
wide range of organic compounds, and possess long shelf lives.[3]
The 2H-benzo[b][1,4]thiazin-3(4H)-one (3) structural motif is characteristic of a
very important class of heterocyclic compounds possessing significant pharmaceuti-
cal and biological properties.[4] Moreover, their industrial[5] and agricultural[6] appli-
cations are also significant. As a result, are currently devoting synthetic chemists
extensive efforts to develop more efficient and simpler methods for the synthesis
of these heterocycles.
Received January 6, 2012.
Address correspondence to A. Sharifi, Chemistry and Chemical Engineering Research Center of
Iran, P. O. Box 14335-186, Tehran, Iran. E-mail: sharifi@ccerci.ac.ir
2079

2080
A. SHARIFI ET AL.
Several routs have been offered so far for the synthesis of benzothiazin-3-ones,
such as cyclization of o-aminothiophenols or their disulfide equivalents with appro-
priately a-substituted carbonyl compounds,[7] replacement of the halogen atom of
halonitrobenzenes with a thiol acetate followed by the reduction of the nitro group
prior to the final annulation step,[8] and the reaction of 2-chloroanilines with sodium
sulfide and then cyclization of the aminothiophenol intermediate with chloroacetic
acid derivatives.[9] Other methods are based on the Smiles rearrangement, which
involves a one-pot reaction of 2-chlorothiophenols with chloroacetyl chlorides and
amines,[10] and ring expansion of appropriate smaller heterocycles.[11] Nevertheless,
many of the reported methods involve more than one-step reactions, require heating
at high temperatures, do not produce good yields of diverse array of products, or
demand the use of commercially unavailable starting materials or reagents. In the
framework of our studies on heterocyclic systems[12] and in continuation of our pre-
vious investigations on the development of environmentally friendly procedures,[13]
we recently communicated a procedure for the one-pot chemoselective synthesis of
2H-benzo[b][1,4]oxazin-3(4H)-one derivatives from their corresponding 2-aminophe-
nols by using 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in the IL [omim][BF4]. In
that work, the IL could be recovered and reused several times without any noticeable
loss of performance. Now, report the improved application of the results to the
[omim][NO3]-mediated annulation of 2-aminothiophenols 1 with 2-bromoalkanoates
2 in the presence of no additive, base, or catalyst (Scheme 1). The procedure offers a
one-pot mild reaction that takes place at room temperature, incorporates a broad
range of starting materials, and provides the possibility of efficiently recycling the IL.
We examined several sets of conditions to optimize the reaction of
2-aminothiophenol 1a with ethyl 2-bromobutanoate 2c, as summarized in Table 1.
Compared to other carbonate bases, K2CO3 showed better performance in several
aqueous mixtures of ILs (entries 1–3) to give product 3ac, although for [omim][NO3]
(entry 4) and [bmim][NO3] (entry 5) very low conversions were observed. Use of
DBU, KF, and Et3N (entries 6–8) could not lead to better results. In the absence
of water, a base, or both, [bmim][BF4] and [omim][BF4] were unable to induce sig-
nificant formation of 3ac (entries 9–12). To our surprise, both [bmim][NO3] (entry
13) and [omim][NO3] (entry 14) showed excellent performance in the absence of
water and bases, leading to high formation of 3ac within 2 h. Conducting the reac-
tion in the absence of any IL gave no product after a long reaction time, proving
the effect of the medium in catalyzing the reaction (entry 15). It is noteworthy
to mention that under the optimized conditions, 2-aminophenols had very poor
participation in similar reactions.
Scheme 1. General pathway for the synthesis of the target products.

GREEN SYNTHESIS OF BENZOTHIAZINONES
2081
Table 1. Optimization of the reaction conditions for the synthesis of 3aa
Entry
Conditions
Time (h)
Yield %a
1
2
[bmim][BF4]=H2O=K2CO3
[omim][BF4]= H2O=K2CO3
[bmim]Cl= H2O=K2CO3
[omim][NO3]= H2O=K2CO3
[bmim][NO3]= H2O=K2CO3
[bmim][BF4]= H2O=DBU
[bmim][BF4]= H2O=KF
[bmim][BF4]= H2O=Et3N
[bmim][BF4]=K2CO3
[bmim][BF4]=H2O
24
24
24
24
24
24
24
24
24
24
24
24
2
98
88
52
18
7
3
4
5
6
48
54
73
33
0
7
8
9
10
11
12
13
14
15
[bmim][BF4]
[omim][BF4]
8
22
83
96
0
[bmim][NO3]
[omim][NO3]
no IL
2
24
aIsolated yields.
Next, the optimized conditions ([omim][NO3]=rt) were employed to examine
the generality of the procedure (Table 2). Reactions of the parent 2-aminothiophenol
1a with 2-bromoalkanoates 2a–2d all completed in 2 h and gave good yields of
products 3aa–3ad (entries 1–4). The same reaction with ethyl 2-bromo-2-methylpro-
panoate 2e also gave the respective product 3ae but over a much longer time period,
presumably because of greater steric hindrance of the substrates (entry 5). The
conditions were amenable to the same reaction with 2-bromolactone 2f, giving 3af
in a very short time interval (entry 6). Use of a starting 2-aminothiophenol bearing
an electron-withdrawing substituent (1b) gave good yields of the desired products
(entries 7–12) in a slightly longer time period. This was attributed to relatively poorer
electronic nature of the substrate which has lower nucleophilicity. In contrast, the
electron-releasing 5-methoxy-substituted 1c showed greater reactivity and gave its
respective products 3ca–cf in much shorter time periods (entries 13–18).
In all cases discussed for the synthesis of 1,4-benzothiazinones 3, reactions were
completed at room temperature in relatively short time periods and products were
readily extracted by ether, precipitated by partial removal of the ether content, and
purified by recrystallization from Et2O. This allowed us to save time, solvents, and
adsorbents by avoiding chromatography of the crude reaction mixtures. In addition,
the IL was recovered and reused in subsequent reactions without significant loss of
activity as shown in five consecutive reactions of 1a with 2a (Fig. 1, top). Comparison
of the 1H NMR spectra of the IL before the reaction and after recovery=decoloriza-
tion process showed no significant deterioration in the quality of the IL, as shown in
Fig. 1, bottom.
Comparison of the results with previous related methods[7–11] clearly confirms
the superiority of the current procedure, where all primary, secondary, and tertiary
2-bromoalkanoates react to give good yields of benzothiazinones in short time
periods. A better conclusion can be reached at by the comparison of the results of
the present work with those of some other recent procedures, as summarized in
Table 3 for products 3aa and 3ab.

2082
A. SHARIFI ET AL.
Table 2. [Omim][NO3]-catalyzed synthesis of products 3
Entry
1
o-Aminothiophenol
1a
2-Bromoalkanoate
2a
Product
Time (h)
2
Yield %a
98
2
1a
2b
2
88
3
4
1a
1a
2c
2
2
92
90
2d
5
1a
2e
20
94
6
7
1a
1b
2f
1
2
90
92
2a
8
9
1b
1b
1b
1b
2b
2c
2d
2e
3
3
88
90
88
90
10
11
3
24
12
13
1b
1c
2f
6
82
90
2a
0.25
14
15
1c
1c
2b
2c
0.75
0.75
94
95
(Continued )

GREEN SYNTHESIS OF BENZOTHIAZINONES
2083
Table 2. Continued
Entry
16
o-Aminothiophenol
1c
2-Bromoalkanoate
2d
Product
Time (h)
0.75
Yield %a
95
17
18
1c
1c
2e
2f
4
2
80
80
aIsolated yields.
Figure 1. Efficient recovery of the IL (top); 1H NMR spectra of fresh and recovered [omim][NO3]
(bottom).

2084
A. SHARIFI ET AL.
Table 3. Comparison of the present procedure with some other recent methods
Product
Conditions
Yield (%)
Reference
3aa
3aa
3aa
3aa
3aa
3ab
3ab
3ab
[Omim][NO3], rt, 2 h
98
94
This work
KF=alumina=IL, 85 ꢀC, 2.5 h
SmI2, dry THF, 2 h
EtOH, HCl, reflux, 2 steps
Chhikara et al.[14]
Zhong et al.[15]
Cabiddu et al.[16]
Borate et al.[17]
This work
83
60
DCM, K2CO3, EtOAc, rt to reflux, 14 h, 2 steps
[Omim][NO3], rt, 2 h
DBU, NMP,a MW, 180 ꢀC, 150 psi, 4 min
EtOH, EtONa, reflux, 3.5 h
Not given
88
98
95
Kamila et al.[18]
´ꢀ
Koos et al.
[19]
aN-Methylpiperidine.
Besides the recovery and reusability of the IL, it is very important from an
environmental point of view that the IL in this method is employed without the
use of any other additive or base. Indeed, the IL not only dissolves the reactants here
but also initiates the reaction by the basicity of its anion and catalyzes the nucleophi-
lic addition of the thiolate to the carbonyl moiety by its coordinative ability. ILs
with nitrate ion as their anionic component are known to exhibit strong basicity
and coordination abilities and therefore can initiate the reaction by deprotonation
of the starting thiophenol.[20] This can justify lack of participation of the less acidic
aminophenols when they were subjected to the same reaction conditions.
Based on these, a mechanism can be offered for the procedure where initial
deprotonation of the thiol group of the 2-aminothiophenol by the anion of the IL
provides the thiophenolate required to attack the electrophilic substrates 2 (or 4).
The ionic liquid as a polar aprotic solvent promotes this process by helping the
dissociation of the relatively highly acidic proton of the thiol group. In addition,
the affinity of the nitrate ion for hydrogen bonding[21] with thiophenol increases
the ease of deprotonation. The reaction is then followed by in situ annulation of
the intermediate A to give the product (Fig. 2). The mechanism is supported by
0
=
=
separation and characterization of the intermediate A (where R R ¼ Me, X Cl).
Therefore, it is not surprising that in the presence of water that the efficiency of the
Figure 2. Proposed mechanism.

GREEN SYNTHESIS OF BENZOTHIAZINONES
2085
reaction is diminished (even with K2CO3; Table 1, entries 4 and 5) because the basicity
of the nitrate ion is lowered due to hydrogen bonding with water molecules.[21]
In summary, the present procedure takes place at room temperature, annula-
tions of 2-aminothiophenols with 2-bromoalkanotes of different steric bulk occur
in one pot, reactions are chemoselective, good yields of products are obtained in rela-
tively short time periods, and the IL can be recovered at the end of the process and
reused efficiently in the next reactions without any noticeable loss of activity. More-
over no chromatography is required for separation of the products because they
could be directly obtained from the crude extracts by concentration of the content.
The generality of the reaction and efficient engagement of a variety of the reactants
in the procedure make it an interesting and green addition to the present literature
archive. Study of the annulation in similar heterocyclic systems is currently under
investigation in our laboratory.
EXPERIMENTAL
Reactions were monitored by thin-layer chromatography (TLC) using silica
gel–coated plates and EtOAc=hexane solutions as the mobile phase. Melting points
are uncorrected. Fourier transform–infrared (FT-IR) spectra were recorded using
KBr disks on a Bruker Vector-22 IR spectrometer and absorptions are reported as
1
wave numbers (cmꢁ1). H NMR (500 MHz) and 13C NMR (125 MHz) spectra were
obtained on a FT-NMR Bruker Ultra Shield instrument as CDCl3 solutions and
the chemical shifts are expressed as d units with Me4Si as the internal standard. Mass
spectra were obtained on a Finnigan Mat 8430 apparatus at ionization potential of
70 eV. Elemental analyses were performed using a Thermo Finnigan Flash EA
1112 instrument. ILs were prepared using available procedures.[22] The recovery of
the IL was performed by removing its ether content (under reduced pressure at
50 ꢀC for 1 h using a rotary evaporator). Reagents were purchased from commercial
sources and were freshly used after being purified by standard procedures. The ident-
ity of the known products was confirmed by the comparison of their melting points
and their NMR data with those available in the literature.[4b,7b,14,18,23,24] New
1
products were characterized by their H NMR, 13C NMR, IR, and mass spectra,
and their purity was confirmed by elemental analyses.
Synthesis of 1-Octyl-3-methylimidazolium Nitrate ([Omim][NO3])
[Omim][NO3] was synthesized according to a two-step literature procedure[22d,e]
used for the synthesis of [bmim][NO3] except that 1-bromooctane (19.3 g, 100 mmol)
was used instead of 1-bromobutane. The product was obtained as an oil and the over-
all yield was 84% (21.6 g).
Typical Procedure
A mixture of 1 (1.0 mmol) and 2 (1.0 mmol) in [omim][NO3] (218 mL, 1 mmol) in
a flask was stirred at room temperature for an appropriate length of time. After com-
pletion of the reaction, based on TLC monitoring, the reaction mixture was extracted
with diethyl ether. The organic phase was washed with brine, dried over anhydrous

2086
A. SHARIFI ET AL.
Na2SO4, and concentrated under reduced pressure to obtain the solid product, which
was further purified by recrystallization from ether. The IL was recovered by remov-
ing its volatiles under reduced pressure at 80 ꢀC and reused in next reactions without
losing its activity.
7-Chloro-2-(2-hydroxyethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (3bf)
1
White solid, mp 132–133 ꢀC; H NMR (500 MHz, CDCl3) d 8.94 (br s, 1H),
7.35 (d, J ¼ 2.2 Hz, 1H), 7.18 (dd, J ¼ 2.2, 8.5 Hz, 1H), 6.85 (d, J ¼ 8.5 Hz, 1H),
3.89–3.81 (m, 2H), 3.73 (t, J ¼ 7.4 Hz, 1H), 2.21–2.17 (m, 1H), 1.96 (br s, 1H),
1.95–1.89 (m, 1H); 13C NMR (125 MHz, CDCl3) d 167.9, 135.8, 128.2, 127.7,
127.2, 120.5, 118.4, 58.9, 39.4, 32.8; IR (KBr) cmꢁ1 3404, 3197, 2953, 1662, 1475,
1244, 813, 651; EI-MS (m=z) 243 [Mþ] 212, 170, 95. Elemental analyses calcd. for
C10H10ClNO2S: C, 49.28%; H, 4.14; N, 5.75; S, 13.16. Found: C, 49.37%; H, 4.18;
N, 5.88; S, 13.20.
7-Methoxy-2-methyl-2H-benzo[b][1,4]thiazin-3(4H)-one (3cb)
1
White solid: mp 126–127 ꢀC; H NMR (500 MHz, CDCl3) d 9.03 (br s, 1H),
6.87 (d, J ¼ 2.5 Hz, 1H), 6.86 (d, J ¼ 8.5 Hz, 1H), 6.76 (dd, J ¼ 2.5, 8.5 Hz, 1H),
3.81 (s, 3H), 3.57 (q, J ¼ 7.1 Hz, 1H), 1.52 (d, J ¼ 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 169.3, 156.3, 130.2, 120.8, 118.5, 113.8, 113.2, 56.1, 37.6,
16.0. IR (KBr) cmꢁ1 3199, 2966, 1664, 1498, 1228, 810, 569; EI-MS (m=z) 209
[Mþ], 194, 166, 150. Elemental analyses calcd. for C10H11NO2S: C, 57.39%; H,
5.30; N, 6.69; S, 15.32. Found: C, 57.21%; H, 5.38; N, 6.57; S, 15.33.
2-Ethyl-7-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (3cc)
1
White solid, mp 113–115 ꢀC; H NMR (500 MHz, CDCl3) d 9.27 (br s, 1H),
6.87 (d, J ¼ 2.5 Hz, 1H), 6.85 (d, J ¼ 8.0 Hz, 1H), 6.75 (dd, J ¼ 2.5, 8.0 Hz, 1H),
3.81 (s, 3H), 3.34 (dd, J ¼ 6.0, 8.8 Hz, 1H), 2.02–1.93 (m, 1H), 1.71–1.62 (m, 1H),
1.10 (t, J ¼ 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 168.5, 156.3, 130.1, 120.1,
118.3, 113.7, 113.4, 56.0, 45.0, 23.7, 11.8; IR (KBr) cmꢁ1 3180, 2954, 1670, 1494,
1232, 869, 621; EI-MS (m=z) 223 [Mþ], 194, 166, 150. Elemental analyses calcd.
for C11H13NO2S: C, 59.17%; H, 5.87; N, 6.27; S, 14.36. Found: C, 59.53%; H,
5.87; N, 6.20; S, 14.30.
7-Methoxy-2-propyl-2H-benzo[b][1,4]thiazin-3(4H)-one (3 cd)
White solid, mp 115–118 ꢀC; 1H NMR (500 MHz, CDCl3) d 9.35 (br s, 1H), 6.87
(d, J ¼ 2.5 Hz, 1H), 6.86 (d, J ¼ 8.5 Hz, 1H), 6.75 (dd, J ¼ 2.5, 8.5 Hz, 1H), 3.81 (s,
3H), 3.43 (dd, J ¼ 2.9, 6.0 Hz, 1H), 1.92–1.88 (m, 1H), 1.65–1.58 (m, 2H), 1.58–1.47
(m, 1H), 0.95 (t, J ¼ 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 168.6, 156.3,
130.1, 120.2, 118.3, 113.6, 113.4, 56.0, 43.0, 32.2, 20.3, 13.9; IR (KBr) cmꢁ1) 3170,
3064, 2939, 1664, 1490, 813, 597; EI-MS (m=z) 237 [Mþ], 195, 166, 151. Elemental
analyses calcd. for C12H15NO2S: C, 60.73%; H, 6.37; N, 5.90; S, 13.51. Found: C,
60.78%; H, 6.44; N, 5.84; S, 13.39.

GREEN SYNTHESIS OF BENZOTHIAZINONES
2087
2-(2-Hydroxyethyl)-7-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (3cf)
1
White solid, mp 138-140 ꢀC; H NMR (500 MHz, CDCl3) d 9.12 (br s, 1H),
6.87 (d, J ¼ 2.5 Hz, 1H), 6.86 (d, J ¼ 8.5 Hz, 1H), 6.75 (dd, J ¼ 2.5, 8.5 Hz, 1H),
3.88–3.82 (m, 2H), 3.80 (s, 3H), 3.70 (t, J ¼ 7.4 Hz, 1H), 2.42 (br s, 1H), 2.21–2.14
((m, 1H), 1.96–1.89 (m, 1H); 13C NMR (125 MHz, CDCl3) d 168.7, 156.5, 129.8,
120.4, 118.5, 113.9, 113.4, 60.1, 56.0, 40.2, 33.1; IR (KBr) cmꢁ1 3412, 3192, 1672,
1494, 1232, 817, 603; EI-MS (m=z) 240 [Mþ], 209, 167, 124, 56. Elemental analyses
calcd. for C11H13NO3S: C, 55.21%; H, 5.48; N, 5.85; S, 13.40. Found: C, 55.27%; H,
5.64; N, 5.62; S, 13.46.
Intermediate A
1H NMR (500 MHz, CDCl3) d 7.33 (d, J ¼ 2.4 Hz, 1H), 7.15 (dd, J ¼ 8.6 Hz,
2.4 Hz, 1H), 6.72 (d, J ¼ 8.6 Hz, 1H), 4.16 (s, 1H), 4.13 (q, 2H), 1.55 (s, 6H), 1.24
(t, 3H).
ACKNOWLEDGMENT
The authors gratefully thank the Iran National Science Foundation (INSF) for
financial support of this work (Project 88000118).
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